This invention relates to novel compositions of matter containing optically pure (R,R) formoterol. These compositions possess potent, long-lasting bronchodilating activity as .beta.-adrenergic agonists while avoiding or reducing adverse effects including but not limited to muscle tremor and tachycardia as well as avoiding or reducing the development of tolerance or hypersensitivity on repeated administration. The compositions also provide an improved duration of action. This invention also relates to methods of treating asthma, bronchitis, emphysema, bronchospasms, and other ailments in patients with obstructive airway or allergic disorders while avoiding adverse effects, development of tolerance or hypersensitivity on repeated administration or a limited pattern of bronchial distribution when administered by inhalation.
The active compound of these compositions and methods is an optical isomer of formoterol, which is described by Ida in Arzneim, Forsch. 26, 839-842 and 1337-1340 (1976) and in U.S. Pat. No. 3,994,974. Chemically, the active compound is N-hydroxy-5-(l-hydroxy-2-[(2-(4-methoxyphenyl) methylethyl]amino]ethyl]phenylformamide, which exists as two enantiomeric pairs of diastereomers. Of these, the R,R diastereomer is the most active and, when substantially optically pure, will be hereinafter referred to as (R,R) formoterol. Formoterol is available commercially only as a racemic diastereomer, (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterol refers to this enantiomeric mixture. The racemic mixture of (.+-.) formoterol that is commercially available for administration is a dihydrate of the furmarate salt.
When two chiral centers occur in the same molecule each of them can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers which share chemical properties and melting points just like any other enantiomeric pair. (R,S) and (S,R) are similarly and enantiomeric pair. The mirror images of (R,R) and (S,S) are not however, superimposable on (R,R) and (S,S). This relationship is called diastereomeric, and (R,R) is a diastereomer of (R,S). Formoterol, having two chiral centers, falls into this category.
Adrenergic or sympathomimetic drugs are so called because they are understood to exert their effect through their action on the body's adrenergic receptors of which there are three functionally divided types, the .alpha., .beta..sub.1 and .beta..sub.2 receptors. On the basis of their interaction with these three receptor types, the adrenergic or sympathomimetic drugs are in turn classifiable into three groups:
1.1 Non-selective sypathomimetic drugs; PA1 1.2 Non-selective .beta. sympathomimetic drugs; and PA1 1.3 Selective .beta..sub.2 sympathomimetic bronchodilator drugs.
Drugs of group 1.1 exert both .alpha. and .beta. sympathomimetic effects. They include the drug substances adrenaline and ephedrine. Both adrenaline and ephedrine are known clinically as bronchodilators. Though adrenaline, despite side effect induced via its .alpha.-sympathomimetic properties, is still used by some practitioners for the treatment of acute asthma, both adrenaline and ephedrine have been largely superseded in asthma therapy.
The drugs of group 1.2 have both .beta..sub.1 and .beta..sub.2 sympathomimetic activity but no, or only limited, .alpha.-sympathomimetic activity. Of the group 1.2 drugs, isoprenaline is the best known representative. Isoprenaline differs from the drugs of group 1.3 in its faster onset but shorter duration of action and its cardiac stimulating effects which result largely from its .beta..sub.1 activity. Though isoprenaline has previously been extensively used as bronchodilator therapy in asthma, its use has today become clinically restricted. Thus, in the UK, a rise in the rate of asthma death in the 1960's believed to have been specifically associated with isoprenaline usage has resulted in discontinuation of its clinical application.
The selective .beta..sub.2 sympathomimetic bronchodilator drugs of group 1.3 (herein referred to for convenience collectively as "Group 1.3 drugs") act, as their name implies, selectively on the .beta..sub.2 adrenergic receptors. The Group 1.3 drugs include for example, the drug substances terbutaline, albuterol, fenoterol, isoetharine, metaproterenol and, more recently, the so-called "long acting selective .beta..sub.2 sympathomimetic bronchodilator drug substances" formoterol, bambuterol and salmeterol. All of the above recited Group 1.3 drugs are commercially available and clinically used, generally in pharmaceutically acceptable salt form, e.,g. as the sulphate, hydrobromide, hydrochloride, fumarate or methanesulfonate or, where appropriate, one or other of the hydrate forms thereof.
Group 1.3 drugs characteristically contain as part of their structure and ethanolamine or 2-amino-ethanol moiety of formula I ##STR1##
in which R.sub.1 is an aromatic group. Commonly R.sub.1 is 3,4- or 3,5-dihydroxyphenyl or 4-hydroxy-3-hydroxymethylphenyl. R.sub.1 may also be 3-formylamino-4-hydroxyphenyl, as in the case of formoterol. R.sub.2 and R.sub.3 in formula I are commonly H. Since the formula I moitey comprises at least 1 asymmetric carbon atom (Cl in formula I), all of the Group 1.3 drugs exist in optically active isomeric form, with the chiral carbon atom having the (R) or (S) configuration [as designated using the Cahn-Ingold-Prelog system (Angew. Chem. Itern. Ed. 5, 385-415 (1966)]. When the C1 carbon atom is the sole asymmetric carbon atom present, Group 1.3 drugs thus exist as individual (R) or (S) enantiomers or in racemic [(RS)] form, i.e. as a 50:50 mixture of the (R) and (S) enantiomers.
Individual Group 1.3 drugs in which R.sub.2 in the formula I moiety is other than H, or in which the remainder of the molecule includes an asymmetric carbon atom (e.g. formoterol) exist in a variety of isomeric forms, i.e. in individual (R,R), (S,S,) (R,S) and (S,R) isomeric form, as racemic [(RS,RS) and (RS,SR)] mixtures comprising the (R,R) plus (S,S) plus (S,S) and (R,S) plus (S,R) enantiomeric pairs, as well as in the form of diastereomeric mixtures comprising all four isomeric forms.
The Group 1.3 drugs can be administered orally, parenterally or (most commonly) by inhalation, e.g. using nebulizers or metered aerosol devices or as inhaled powders. Inhalation of Group 1.3 drugs presently represents the mainstay of bronchodilator therapy for the treatment of asthma of all grades of severity. The duration of bronchodilatation induced by the majority of Group 1.3 drugs is relatively short and they are employed to relieve asthma attack as and when it occurs. As indicated above, the more recently introduced Group 1.3 drugs, such as formoterol, are characterized by their longer duration of action and hence apparent reduced frequency of dosaging required.
Although the Group 1.3 drugs are effective and generally seem to be well tolerated, their safety, especially at high dosages, has been questioned over many years and numerous reports have appeared on the adverse effects of Group 1.3 drug therapy (see e.g. Paterson et al: American Review of Respiratory Disease 120, 844-1187 (1979) especially at page 1165 et seq.). More recently, from New Zealand, where a continuing increase in asthma death has been recorded, two case control studies reported in The Lancet have linked increase in asthma mortality to use of the Group 1.3 drug, fenoterol--see in particular: Editorial ".beta..sub.2 agonists in asthma: relief, prevention, morbidity", Lancet 336, 1411-1412 (1990). A subsequently reported Canadian study finds that the use of inahaled Group 1.3 drugs, principally fenoterol and albuterol, is associated with "an increased risk of the combined outcome of fatal and near-fatal asthma, as well as of death from asthma alone"--see Spitzer et al., New England J. Med. 326 (8), 501-506 (1992) and the Editorial to the same issue at page 560.
Various possible explanations for observed episodes of increased airway obstruction, arterial hypoxaemia or "anamalous" or "paradoxical" bronchospasm, as well as increased morbidity associated with Group 1.3 drug usage, in particular long term/high dose usage, have been proposed. These have included, for example, reactive myogenic tone, increased inflammatory burden, adrenoceptor tachyphylaxis and induction of airway hyperreactivity, as well as the involvement of spasmogenic drug metabolic products or long term influence of aerosol spray propellants--see e.g. Paterson et al. loc. cit. and Morley et al., Eur. Respir. J. 3, 1-5 (1990).
There is mounting concern within the medical profession as to the potential dangers of Group 1.3 drug usage in asthma therapy. To quote the Lancet editorial already referred to:
"These studies raise serious question about the use of .beta.2 agonists [i.e. Group 1.3 drugs]. The findings of Sears et al. could be interpreted as supporting the current trend towards earlier use of corticosteroids and other preventers of inflammation [for asthma therapy] rather than perseverance with an escalating bronchodilator regimen. The findings of the Nottingham and Dunedin groups also indicate that there is some way to go before long acting .beta.2 agonist preparations such as salmetreol and formoterol can be unreservedly recommended for routine use in the management of asthma. There seem to be clear advantages of compliance and possibly of anti-inflammatory activity associated with such agents, but the potential for adverse effects cannot be ignored. Clinicians researchers and pharmaceutical companies must now attempt to redefine the use of .beta.2 agonists in asthma." [Emphasis added.]
Equally there has been evident inability or reluctance to conceive of any problem in relation to Group 1.3 drug therapy as being inherent in Group 1.3 drugs themselves or as hitherto employed--cf. the following, taken from the editorial in the New England Journal of Medicine also previously referred to:
"Although . . . too much reliance is placed on beta-agonists (Group 1.3 drugs], it is difficult to believe that the problem is related directly to the more regular use of inhaled beta-agonists."
While the suitability, in particular of high-dose or long-term, Group 1.3 drug therapy has long been a subject of debate and, more recently, acute question, the practice of administering drugs of this group as racemic mixtures has continued. This practice has been accepted by drug registration authorities world-wide and even the most recently introduced of the Group 1.3 drugs have been developed for clinical use as racemic mixtures. This practice is based upon the assumption or understanding that the non-bronchodilator component of the racemic mixture, i.e. the bronchodilatorily less or inactive enantiomer (distomer) is devoid of any relevant drug effect and can thus be administered together with the bronchodilatorily active isomer (eutomer) essentially as inactive ballast and without risk to the patient. The teaching of the present invention thus stands in stark opposition to long, widely established and continuing practice. The present invention thus runs contrary to the wisdom of the art. In that the Group 1.3 drugs clearly offer very considerable potential benefit for bronchodilator usage in asthma, the need to find a means of avoiding, ameliorating or restriction disadvantages inherent in their use is urgent and crucial. By meeting this need, the present invention may be anticipated to bring immeasurable benefit both to the medical profession and the world asthma population.
Formoterol, which is the subject of the present invention, is available only as a racemic mixture of the (R,R) and (S,S) diastereomers. Trofast et al. [Chirality 3, 443-450 (1991)] have described the preparation of each of the substantially pure isomers. They concluded that "Since the (S,S)-enantiomer is practically inactive there is from this point of view no reason for its removal from the racemate in phamaceutical preparations . . . "
Formoterol's primary use is as a long-acting bronchodilator for the relief of reversible bronshospasm in patients with obstructive airway disease such as asthma, bronchitis and emphysema.
Asthma, bronchitis and emphysema are known as Chronic Obstructive Pulmonary diseases (COPD). COPD is characterized as generalized airways obstruction, particularly of small airways, associated with varying degrees of symptoms of chronic bronchitis, asthma, and emphysema. The term COPD was introduced because these conditions often coexist, and it may be difficult in an individual case to decide which is the major condition producing the obstruction. Airways obstruction is defined as an increased resistance to airflow during forced expiration. It may result from narrowing or obliteration of airways secondary to intrinsic airways disease, from excessive collapse of airways during a forced expiration secondary to pulmonary emphysema, from bronchospasm as in asthma, or may be due to a combination of these factors. Although obstruction of large airways may occur in all these disorders, particularly in asthma, patients with severe COPD characteristically have major abnormalities in their small airways, namely those less than 2 mm internal diameter, and much of their airways obstruction is situated in this zone. The airways obstruction is irreversible except for that which can be ascribed to asthma.
Asthma is a reversible obstructive lung disorder characterized by increased responsiveness of the airways. Asthma can occur secondarily to a variety of stimuli. The underlying mechanisms are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airways diameter has been implicated. Persons manifesting such imbalance have hyperactive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such persons-are subjected to various stresses, such as viral respiratory infection, exercise, emotional upset, nonspecific factors (e.g., changes in barometric pressure or temperature), inhalation of cold air or irritants e.g., gasoline fumes, fresh paint and noxious odors, or cigarette smoke), exposure to specific allergens, and ingestion of aspirin or sulfites in sensitive individuals. Psychologic factors may aggravate an asthmatic attack but are not assigned a primary etiologic role.
Persons whose asthma is precipitated by allergens (most commonly airborne pollens and molds, house dust, animal danders) and whose symptoms are IgE-mediated are said to have allergic or "extrinsic" asthma. They account for about 10 to 20% of adult asthmatics; in another 30 to 50%, symptomatic episodes seem to be triggered by non-allergenic factors (e.g., infection, irritants, emotional factors), and these patients are said to have nonallergic or "intrinsic" asthma. In many persons, both allergenic and nonallergenic factors are significant. Allergy is said to be a more important factor in children than in adults, but the evidence is inconclusive.
Chronic bronchitis (unqualified) is a condition associated with prolonged exposure to nonspecified bronchial irritants and accompanied by mucus hypersecretion and certain structural changes in the bronchi. Usually associated with cigarette smoking, it is characterized clinically by chronic productive cough. The term chronic obstructive bronchitis is used when chronic bronchitis is associated with extensive abnormalities of the small airways leading to clinically significant airways obstruction. (Pulmonary emphysema is enlargement of the air spaces distal to terminal nonrespiratory bronchioles, accompanied by destructive changes of the alveolar wall.) The term chronic obstructive emphysema is used when airways obstruction is also present and where it is clear that the major features of the disease can be explained by emphysematous changes in the lungs.
Many of the .beta..sub.2 agonists cause somewhat similar adverse effects. These adverse effects include but are not limited to the central nervous system symptoms such as hand tremors, muscle tremors, nervousness, dizziness, headache and drowsiness; respiratory side effects such as dyspnea, wheezing, drying or irritation of the oropharynx, coughing, chest pain and chest discomfort; cardiovascular effects such as palpitations, increased heart rate, and tachycardia. According to Trofast et al. (op. cit.) (R,R) formoterol is primarily a chronotropic agent in vitro with inotropic effects showing up at higher concentrations. The chronotropic effects are reported at concentrations that are higher than those at which relaxation of tracheal muscle (bronchodilation) is seen. .beta.-Agonists (e.g. dobutamine) are known in general to exhibit inotropic activity. In addition, racemic .beta..sub.2 -agonists can cause angina, vertigo, central stimulation and insomnia, airway hyperreactivity (hypersensitivity), nausea, diarrhea, dry mouth and vomitting. As with other pharmaceuticals .beta..sub.2 -agonists sometimes cause systemic adverse effects such as weakness, fatigue, flushed feeling, sweating, unusual taste, hoarseness, muscle cramps and backaches.
Furthermore, patients have a tendency to develop a tolerance to the bronchodilating effect of the racemic mixture of formoterol. This is related to desensitization, which is one of the most clinically significant phenomena involving the beta-adrenergic receptor. It has been observed that patients in prolonged beta-agonist therapy have a tendency to increase the dosage of drug they use. This occurs because after prolonged administration, the beta-receptor appears to become desensitized to the agonist, thus requiring larger doses of the compound to effect an equivalent physiological response.
The problem of desensitization is especially significant in the treatment of diseases involving bronchospasms, such as asthma. The treatment of asthma usually involves the self-administration either orally or by aerosol, of beta-adrenergic agonists such as the racemic (R,R) (S,S) mixture of formoterol. These agonists mediate bronchodilation and promote easier breathing. Asthmatic patients utilizing .beta.-agonists for a prolonged time gradually increase the self-administered dose in order to get a sufficient amount of bronchodilation and relief in breathing. As a result of this increased dosage, the agonist concentration builds to a sufficient level so as to enter the peripheral circulation where it acts on the beta receptors of the heart and vasculature to cause cardiovascular stress and other adverse effects.
Moreover, when administering the racemic mixture of formoterol by inhalation, because of particle size and air flow distribution characteristics of the racemic mixture of formoterol, the distribution of the compound into the smaller bronchioles is limited, which results in a decreased effectiveness of the compound.
It is therefor desirable to find a compound with the therapeutic characteristics of formoterol which would not have the above described disadvantages.